Efficient detection and clearance of apoptotic cells is critical for control of tissue homeostasis. Professional phagocytes are responsible for removal of dying cells; however, defects in recognition or engulfment of apoptotic cells can lead to chronic inflammation and autoimmune disease. Accumulation of apoptotic cells in tissues has been associated with the autoimmune disease systemic lupus erythematosus (SLE), and several receptors on phagocytes responsible for apoptotic cell clearance have been identified. We recently discovered that the scavenger receptor SCARF1 plays an important role in sensing and engulfment of apoptotic cells. Dendritic cells use SCARF1 to capture apoptotic cells via C1q bound to exposed phosphatidylserine, a primary eat me signal that translocates from the inner to the outer leaflet of the cell membrane on dying cells. Scarf1 deficiency in mice leads to the accumulation of apoptotic cells in tissues and the spontaneous development of lupus-like autoimmune disease with the production of autoantibodies to chromatin, aberrant immune cell activation, dermatitis and nephritis. Our previous findings fill several major gaps in our understanding of apoptotic cell clearance and regulation of autoimmunity; however, additional work is needed to identify the mechanisms necessary for SCARF1-mediated removal of apoptotic cells and prevention of spontaneous autoimmunity in vivo. Because apoptotic cell clearance requires numerous receptors and bridging molecules in vivo, we hypothesize that the immune system has developed failsafe mechanisms involving multiple receptors and bridging proteins expressed by different cell types present in specific tissues for the removal of dying cells to maintain tolerance and prevent autoimmunity. To test these hypotheses we will, (1) determine the cell/tissue-specific role of Scarf1 deficiency in the spontaneous development of autoimmune disease; (2) determine the relative contribution of SCARF1, CD36 and C1q to apoptotic cell clearance and prevention of autoimmune disease; (3) define the domains in SCARF1 that mediate apoptotic cell recognition, phagocytosis, and signaling. Understanding the mechanisms by which discrete cell populations use SCARF1 to engulf apoptotic cells and prevent inflammation should enable the design of novel tailored drugs for autoimmune disorders by targeting SCARF1 in specific cell subsets.